Background: Pancreatic cancer is being increasingly associated with germline implications. Some large single-center studies have reported results ranging from 3.9% to 19.8% of patients found to have germline variants [Shindo, JCO 2017; Lowery, JNCI 2018]. Due to this wide range, we aim to further delineate prevalence of deleterious germline mutations in pancreatic cancer using a multi-institutional data set. We also aim to analyze predictive factors such as mutant allele frequency (MAF, in %) in germline versus somatic calls.

Methods: We sequenced 23 genes in DNA prepared from clinical tissue and blood specimens submitted to Tempus Labs. Germline variants and somatic variants were processed separately. Germline variants were determined to be deleterious through the sum effect of a combination of in silico predictors, population databases, and internal evaluations. Tumor-normal comparisons were used to define somatic versus germline, and MAFs were calculated for each.

Results: A total of 234 patient samples from 17 institutions were analyzed. Of these, 12 (5.1%) had predicted deleterious germline variants involving 8 different genes: BRCA1 (n = 3), CHEK2 (n = 3), ATM (n = 1), MLH1 (n = 1), MUTYH (n = 1), PALB2 (n = 1), SMAD4 (n = 1), TP53 (n = 1). For most somatic alterations, the MAFs were found to be greater than the germline deleterious alterations, with the latter approaching ~50% in most cases.

Conclusions: This multi-institutional study identifies 5% of patients with pancreatic cancer to have deleterious germline alterations. Somatic variant testing, particularly when paired with germline, can be used as a screening method for genetic counseling referrals, especially with MAF analyses of paired tumor-normal samples.

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